Late Onset Blinatumomab-Related Neurotoxicity in a Child with B-Cell Acute Lymphoblastic Leukemia

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Data may be preliminary. 4 June 2025 V1 Latest version Share on Late Onset Blinatumomab-Related Neurotoxicity in a Child with B-Cell Acute Lymphoblastic Leukemia Authors : Krunal Shah [email protected] , Harish Tandra , Ulrike Loebel , Marios Kaliakatsos , Jack Bartram 0000-0003-1573-2506 , Philip Ancliff , Sara Ghorashian , … Show All … , Vesna Pavasovic , Danny Cheng , Sujith Samarasinghe , David O'Connor , Ajay Vora , and Anupama Rao Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.174903861.15376932/v1 Published Pediatric Blood & Cancer Version of record Peer review timeline 422 views 186 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract We describe a case of a 14-year-old girl with B-Cell Acute Lymphoblastic Leukemia who developed delayed severe neurotoxicity in her first blinatumomab cycle. Clinical features included encephalopathy and focal neurological deficits. MRI and CSF findings were consistent with immune-mediated neuroinflammation. Following discontinuation of blinatumomab and initiation of dexamethasone therapy, the patient made a complete neurological recovery within five days. This case underscores the potential for delayed onset of blinatumomab-associated neurotoxicity, emphasizing the importance of clinical vigilance beyond the commonly observed early infusion period. Early recognition, prompt cessation of therapy, and initiation of corticosteroids are critical for full neurological recovery. Title: Late Onset Blinatumomab-Related Neurotoxicity in a Child with B-Cell Acute Lymphoblastic Leukemia Authors: Krunal Shah, Harish Tandra, Ulrike Loebel, Marios Kaliakatsos, Jack Bartram, Philip Ancliff, Sara Ghorashian, Vesna Pavasovic, Danny Cheng, Sujith Samarasinghe, David O’Connor, Ajay Vora, Anupama Rao Affiliations of all authors: Great Ormond Street hospital for children, NHS foundation trust, London, United Kingdom Corresponding author information: Krunal Shah e-mail – [email protected] Address- Great Ormond Street hospital for children, Guilford St, London WC1N 3BH Word count for the Abstract: 99 Word count for the main text: 858 Number of figures – 2 Running title: Blinatumomab induced late neurotoxicity Keywords: Blinatumomab, Neurotoxicity, Pediatric Leukemia, B cell Leukemia, Immunotherapy Abbreviation Key MRD measurable residual disease CSF Cerebro spinal fluid FLAIR fluid-attenuated inversion recovery Abstract We describe a case of a 14-year-old girl with B-Cell Acute Lymphoblastic Leukemia who developed delayed severe neurotoxicity in her first blinatumomab cycle. Clinical features included encephalopathy and focal neurological deficits. MRI and CSF findings were consistent with immune-mediated neuroinflammation. Following discontinuation of blinatumomab and initiation of dexamethasone therapy, the patient made a complete neurological recovery within five days. This case underscores the potential for delayed onset of blinatumomab-associated neurotoxicity, emphasizing the importance of clinical vigilance beyond the commonly observed early infusion period. Early recognition, prompt cessation of therapy, and initiation of corticosteroids are critical for full neurological recovery. Introduction Blinatumomab has revolutionized the treatment of relapse/refractory (r/r) B-Cell Acute Lymphoblastic Leukemia (B-ALL). It is a bispecific T cell–engager antibody that redirects the T cells to target CD19 positive B cells (1). It has proven efficacy to achieve a deeper remission albeit with a risk of neurotoxicity (2). In this report, we present a case of a child with B-ALL who developed late onset severe neurotoxicity with blinatumomab infusion. Case Description A 14-year-old girl was diagnosed with B-ALL without central nervous system involvement. Cytogenetic analysis revealed high hyper-diploidy and deletion of IKZF1. She received upfront Blinatumomab for persistent flowcytometry based measurable residual disease (MRD) of 0.031%; following a UKALL based 4 drug induction chemotherapy On day 25 of blinatumomab, cycle 1, she presented with fever, headache and neck pain. Subsequently, she became confused and drowsy. She developed left sided weakness and intermittent tremors of right upper and lower limbs. She had abnormal eye movement with intermittent blinking but no seizures. Clinical possibilities of infectious and/or immune mediated neurotoxicity were considered. Blinatumomab infusion was withheld immediately. Dexamethasone and prophylactic levetiracetam were administered along with meropenem, vancomycin and acyclovir. MRI Brain revealed bilateral, relatively symmetric T2 white matter signal changes, most prominent in the superior parietal and frontal white matter with no diffusion restriction. (Fig. 1) Post contrast T1 and fluid-attenuated inversion recovery (FLAIR) images showed global enhancement of the vessels in supratentorial white matter, basal ganglia, thalami, cerebellum and brainstem favoring neurotoxicity. (Fig. 2) Electro-encephalogram findings of background activity in the delta-theta range, with greater slowing over the right hemisphere suggested moderate encephalopathy. Cerebro spinal fluid (CSF) analysis showed pleocytosis with reactive T cells and monocytes and raised CSF protein. CSF immunophenotyping had no detectable aberrant B-Cell leukemia-associated immunophenotype. CSF bacterial and fungal cultures were negative. Viral polymerase chain reaction for herpes, enterovirus, adenovirus, human polyomavirus and parechovirus were negative. CSF Total Neopterin was 155 nmol/L (Normal reference 7-65 nmol/L). The elevated CSF pterins in the neurotransmitter analysis of CSF was suggestive of immune response activation. Serum Anti MOG and Anti Aquaporin 4 antibodies were negative. Her sensorium improved within 36 hours of stopping blinatumomab infusion, and she made a completed neurological recovery in 5 days. A repeat CSF evaluation after 8 weeks revealed resolution of CSF pleocytosis. There was an excellent response to three weeks of blinatumomab with a negative flow as well as molecular MRD on day 15 and day 29. Discussion Blinatumomab is a safe and effective treatment option for children with relapsed/refractory B-ALL. The leukemic disease burden significantly influences the incidence of cytokine release syndrome and neurotoxic adverse events and hence the reported incidence on various trials has been quite variable (3). The estimated pooled incidence rate for neurologic events was 21% in a meta-analysis on safety of blinatumomab in pediatric patients. (4) The mechanism of blinatumomab-induced neurotoxicity is still unknown. Neurological events are presumed to be caused by an inflammatory irritation of the myoendothelium by blinatumomab-activated T-cells, which locally release neurotoxic cytokines which probably causes neuro-endothelium inflammation and blood–brain barrier disruption (5). The neurologic events may manifest as tremor, slurred speech, loss of vibratory sensation, dizziness, confusion, encephalopathy, and seizures. (6) Blinatumomab administered in a front-line setting was found safe and effective in a multicenter study of 105 children and young persons, with only 1 patient developing severe neurotoxicity. (7) In a multicenter retrospective study, which evaluated blinatumomab in children and adolescents with relapsed/refractory B-Cell precursor ALL, out of 39 children treated, 14 (36%) patients experienced neurologic adverse events: 3 patients had seizures, 2 patients displayed tremors, and 2 displayed peripheral neuropathies. One patient reported aphasia and dysarthria associated with tremor and dysmetria, and two patients had multiple neurological adverse events. However, no associated toxic deaths were reported (8). In the case we described, the child had developed encephalopathy with tremors which rapidly improved with dexamethasone therapy. For patients experiencing neurologic toxicities, the median time of an event is usually within the first fourteen days of blinatumomab infusion (4). However, in our case, the onset was on day 25 of starting blinatumomab therapy, which highlights the possibility of a delayed presentation. Blinatumomab has a very short elimination half-life of 1.25 hours, and most toxicities resolve after interrupting the infusion and initiating dexamethasone (9). In our case, the neurological manifestations completely resolved within 5 days of starting dexamethasone. The CSF findings in this case showed pleocytosis with increased reactive T cells. This finding was also reported in a few other studies which noted that the incidence of pleocytosis was 51% in CSF and more frequent after day 15. These studies also noted that CSF pleocytosis had no impact on CNS relapse or neurotoxicity (10) (11). In a report from Greece, a 14year girl with refractory ALL developed neurotoxicity of status epilepticus at 45 days following blinatumomab therapy which was irreversible (12). However, in our case the neurotoxicity was completely reversible with steroid treatment. To conclude, our case highlights the fact that, although uncommon, blinatumomab associated neurotoxicity can occur late in course after starting the therapy. Prompt recognition with early discontinuation of infusion and initiation of dexamethasone therapy will result in complete neurological recovery. References 1. Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, Noppeney R, Viardot A, Hess G, Schuler M, Einsele H. Tumor regression in cancer patients by very low doses of a T cell–engaging antibody. Science. 2008 Aug 15;321(5891):974-7. 2. Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, Diedrich H, Topp MS, Brüggemann M, Horst HA, Havelange V. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood, The Journal of the American Society of Hematology. 2018 Apr 5;131(14):1522-31 3. Chen B, Zou Z, Zhang Q, Chen K, Zhang X, Xiao D, Li X. Efficacy and safety of blinatumomab in children with relapsed/refractory B cell acute lymphoblastic leukemia: A systematic review and meta-analysis. Frontiers in Pharmacology. 2023 Jan 10;13:1032664. 4. Marrapodi MM, Mascolo A, di Mauro G, Mondillo G, Pota E, Rossi F. The safety of blinatumomab in pediatric patients with acute lymphoblastic leukemia: a systematic review and meta-analysis. Frontiers in Pediatrics. 2022 Jul 22;10:929122. 5. Klinger M, Zugmaier G, Nägele V, Goebeler ME, Brandl C, Stelljes M, Lassmann H, von Stackelberg A, Bargou RC, Kufer P. Adhesion of T cells to endothelial cells facilitates blinatumomab-associated neurologic adverse events. Cancer Research. 2020 Jan 1;80(1):91-101. 6. Stein AS, Schiller G, Benjamin R, Jia C, Zhang A, Zhu M, Zimmerman Z, Topp MS. Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors. Annals of hematology. 2019 Jan 30;98:159-67. 7. Hodder A, Mishra AK, Enshaei A, Baird S, Bhuller K, Elbeshlawi I, Bonney D, Clesham K, Cummins M, Vedi A, Gibson B. Blinatumomab for first-line treatment of children and young persons with B-ALL. Journal of Clinical Oncology. 2024 Mar 10;42(8):907-14. 8. Beneduce G, De Matteo A, Stellato P, Testi AM, Bertorello N, Colombini A, Putti MC, Rizzari C, Cesaro S, Cellini M, Barisone E. Blinatumomab in children and adolescents with relapsed/refractory B cell precursor acute lymphoblastic leukemia: a real-life multicenter retrospective study in seven AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) centers. Cancers. 2022 Jan 15;14(2):426. 9. von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O’brien MM, Brethon B, Bhojwani D, Schlegel PG. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Journal of Clinical Oncology. 2016 Dec 20;34(36):4381-9. 10. Ngo D, Tinajero J, Song JY, Ma H, Quirk E, Koller P, Pourhassan H, Agrawal V, Stein AS, Marcucci G, Murphy L. The characterization and the impact of CSF pleocytosis during blinatumomab therapy for adult acute lymphoblastic leukemia. Leukemia & Lymphoma. 2024 Aug 17:1-9. 11. Leib S, Bielorai B, Vernitsky H, Aharony-Tevet Y, Toren A, Jacoby E. Cerebral Spinal Fluid Parameters Following CD19-Targeted Therapies in Children and Young Adults. Journal of Pediatric Hematology/Oncology. 2024 Jan 1;46(1):29-32. 12. Filippidou M, Avgerinou G, Katsibardi K, Gavra M, Pons R, Kattamis A. Delayed‐onset severe neurotoxicity related to Blinatumomab in an adolescent patient with refractory acute lymphoblastic leukemia. Pediatric Blood & Cancer. 2021 Jul;68(7):e29040. Legend Figure 1 MRI Brain (A-I): T2WI shows diffuse bilateral white matter lesions (A) with facilitated diffusion (B). There is involvement of the brainstem (C). Fluid-attenuated inversion recovery (FLAIR) images after contrast administration (D-E) accentuate lesion contrast and depict cerebral and cerebellar leptomeningeal enhancement (white arrows). Post contrast T1WI (F-I) shows enhancement along the trans-ependymal vessels (black arrows) and of the brainstem (arrow outline). Figure 2 MRI Spine (J-L): T2WI (J) shows faint signal changes of the entire spinal cord. T1WI post contrast (K-L) shows central enhancement and leptomeningeal enhancement, best depicted along the conus medullaris (L). Information & Authors Information Version history V1 Version 1 04 June 2025 Peer review timeline Published Pediatric Blood & Cancer Version of Record 23 Jun 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords all immunotherapy neurotoxicity of therapy Authors Affiliations Krunal Shah [email protected] Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Harish Tandra Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Ulrike Loebel Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Marios Kaliakatsos Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Jack Bartram 0000-0003-1573-2506 Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Philip Ancliff Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Sara Ghorashian Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Vesna Pavasovic Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Danny Cheng Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Sujith Samarasinghe Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author David O'Connor Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Ajay Vora Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Anupama Rao Great Ormond Street Hospital for Children NHS Foundation Trust View all articles by this author Metrics & Citations Metrics Article Usage 422 views 186 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Krunal Shah, Harish Tandra, Ulrike Loebel, et al. 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